This invention relates to processes and compositions and methods of use of formulations containing propofol (2,6-diisopropylphenol) and one or more antimicrobial agent.
Formulations containing propofol for injection can be used in clinical settings for production and maintenance of ambulatory anesthesia, neurosurgical anesthesia, neuroanesthesia, pediatric anesthesia, monitored anesthesia care (MAC) sedation, intensive care (ICU) sedation, cardiac anesthesia, and in other clinical situations (see for example, Smith, I., White, P. F., Nathanson, M. and Gouldson, R. (1994) xe2x80x9cPropofolxe2x80x94An update on its clinical use,xe2x80x9d Anesthesiology, 81, 1005-1043).
U.S. Pat. Nos. 4,056,635 and 4,452,817 disclose compositions containing propofol suitable for parenteral administration to produce anesthesia in warm-blooded animals as mixtures of propofol with surfactants such as CREMOPHOR-RH40(trademark), CREMOPHOR-EL(trademark), and TWEEN-8 (trademark) in an aqueous medium that may also contain ethanol or other pharmaceutically acceptable ingredients.
U.S. Pat. No. 4,798,846 discloses sterile propofol compositions containing 1% to 2% propofol alone or dissolved in oil such as arachis oil or ethyl oleate. These formulations are stabilized with surfactants.
A propofol preparation for clinical use is commercially available as DIPRIVAN(copyright) 1% Injection. This contains propofol dissolved in soybean oil as an emulsion stabilized with egg lecithin in water. Each milliliter of this formulation consists of 10 mg/mL of propofol, 100 mg/mL of soybean oil, 22.5 mg/mL of glycerol, 12mg/mL of egg lecithin, and disodium edetate (0.005%). This product formulation requires strict aseptic technique during handling, and a vial of the product can be used only once because of the ease of microbial contamination in a clinical use setting.
Incidences of serious infection in human subjects have been linked to the use of DIPRIVAN. For example, see Nichols, R. L. and Smith, J. W. (1995) xe2x80x9cBacterial Contamination of an Anesthetic Agent,xe2x80x9d New Eng. J. Med., 333(3), 184-185; Tessler, M., Dascal, A., Gioseffini, S., Miller, M. and Mendelson, J. (1992) xe2x80x9cGrowth curves of Staphyloccoccus aureus, Candida albicans and Moraxella osloensis in propofol and other media,xe2x80x9d Can. J. Anaesth. 39(5), 509-511; Ardulno, M. J., Bland, L. A., McAllister, S. K., Aguero, S. M., Villarino, M. E., McNeil, M. M., Jarvis, W. R. and Favero, M. S. (1991) xe2x80x9cMicrobial Growth and Endotoxin Production in the Intravenous Anesthetic Propofol,xe2x80x9d Inf. Control Hosp. Epidem., 12(9), 535-539; Sosis, M. B. and Braverman, B. (1993) xe2x80x9cGrowth of Staphylococcus aureus in Four Intravenous Anesthetics,xe2x80x9d Anesth. Anal. 77, 766-768; Sosis, M. B., Braverman, B. and Villaflor, E. (1995) xe2x80x9cPropofol, but not Thiopental, Supports the Growth of Candida albicans,xe2x80x9d Anesth. Anal. 81, 132-134; Crowther, J., Hrazdil, J., Jolly, D. T., Galbraith, J. C., Greacen, M. and Grace, M. (1996) xe2x80x9cGrowth of Microorganisms in Propofol, Thiopental and a 1:1 Mixture of Propofol and Thiopental,xe2x80x9d Anesth. Anal. 82, 475-478; and Center for Disease Control report, New England Journal of Medicine (1995) Vol. 333, No 3, pp 184-5 and the accompanying editorial in the same issue.
DIPRIVAN can exhibit a thrombogenic potential in clinical use. Symptoms span the range of thrombosis and phlebitis and include incidences of burning, stinging or sensations of pain (see Physicians Desk Reference 1999, page 3416).
U.S. Pat. Nos. 5,714,520, 5,731,355 and 5,731,356 disclose propofol formulations containing disodium edetate as a preservative in amounts sufficient to prevent no more microbial growth than a 10-fold increase over 24 hours after adventitious extrinsic contamination with the microorganisms Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and Candida albicans ATCC 10231. However, this formulation is not considered to be an antimicrobially preserved product under USP standards as exemplified in Sklar, G. E. (1997) xe2x80x9cPropofol and postoperative infections,xe2x80x9d Ann Pharmacother, 31, 1521-3. Edetate may not be effective as a preservative against growth of microorganisms in a DIPRIVAN formulation if challenged by organisms other than those cited above or by higher loads of organisms, i.e., exceeding 100 CFU/mL.
U.S. Pat. No. 6,140,374 discloses the use of a number of antimicrobial agents in propofol containing oil-in-water emulsions including combinations of edetate and benzyl alcohol.
U.S. Pat. No. 6,028,108 discloses a sterile oil-in-water emulsion of propofol and an amount of pentetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination.
U.S. Pat. No. 6,177,477 discloses a sterile oil-in-water emulsion of propofol and an amount of tromethamine (TRIS) sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination.
U.S. Pat. No. 6,147,122 discloses a sterile oil-in-water emulsion of propofol and an amount of sulfite sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious contamination.
Pain on injection of commercial formulations of propofol has been reported to occur in many patients; for example, see Mirakhur, R. K. (1988) xe2x80x9cInduction characteristics of propofol in children: Comparison with thiopentone,xe2x80x9d Anesthesia, 43, 593-598; Stark, R. D., Binks, S. M., Dukta, V. N., O""Connor, K. M., Arnstein, M. J. A., Glen, J. B. (1985) xe2x80x9cA review of the safety and tolerance of propofol (xe2x80x98Diprivanxe2x80x99),xe2x80x9d Postgrad. Med. J., 61 S, 152-156; and Mangar, D. and Holak, E. J. (1992) xe2x80x9cTourniquet at 50 mm Hg followed by intravenous lidocain diminishes hand pain associated with propofol injection,xe2x80x9d Anesth. Analg., 74, 250-252. Even with a low dose of propofol administered for sedation, the incidence of pain can be high; for example, see White, P. F. and Negus, J. B. (1991) xe2x80x9cSedative infusions during local and regional anesthesia: A comparison of midazolam and propofol,xe2x80x9d J. Clin. Anesth., 3, 32-39; and Ghouri, A. F., Ramirez Ruiz, M. A., and White, P. F. (1994) xe2x80x9cEffect of flumazenil on recovery after midazolam and propofol sedation,xe2x80x9d Anesthesiology, 81, 333-339.
The mechanism or mechanisms responsible for venous pain on propofol administration are unknown. No measurable reduction in pain was detected clinically after a change from a CREMOPHOR-EL based propofol formulation to the currently marketed soybean oil and lecithin based formulation; for example, see Mirakhur, R. K. (1988), Stark et al. (1985), Mangar and Holak (1992), White and Negus (1991), and Ghouri et al. (1994) herein.
Pain at the site of injection of propofol may be related to the concentration of propofol; for example, see Smith, I., White, P. F., Nathanson, M. and Gouldson, R. (1994) xe2x80x9cPropofolxe2x80x94An update on its clinical use.xe2x80x9d Anesthesiology, 81, 1005-1043.
Compositions containing 1% and 2% propofol and a mixture of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) in a dispersed oil phase have produced lowered propofol concentrations in an aqueous phase; see for example Babl, J., Doenicke, A., and Monch, V. (1995) xe2x80x9cNew propofol LCT/MCT fat emulsions as solvent. Approach to reducing pain on injection of propofol,xe2x80x9d Eur. Hosp. Pharmacy, 1, 15-21 and Doenicke, A. W., Babl, J., Kellermann, W., Rau, J., and Roizen, M. F. (1996) xe2x80x9cReducing pain during propofol injection: the role of the solvent,xe2x80x9d Anesth. Analg., 82, 472-4.
While the use of medium chain triglycerides in a propofol formulation in human volunteers can lower the incidence of severe or moderate pain on injection relative to that seen after injection of a commercially available propofol formulation, significantly higher amounts of oil (up to 20% w/v MCT, LCT, and vegetable oil) were required to produce the result (see for example Doenicke, A. W., Babi, J., Klotz, U., Kugler, J., O""Connor, M., Rau, J., Roizen, M. F. (1997) xe2x80x9cPharmacokinetics and pharmacodynamics of propofol in a new solvent,xe2x80x9d Anesth. Analg., 85, 1399-403; Babl et al. (1995); and Doenicke et al. (1996 and 1997).
In an experimental rat model Cox et al. (1998) xe2x80x9cInfluence of different fat emulsion-based intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol,xe2x80x9d Pharmaceutical Research, 15 (3), 442-448 found that the pharmacokinetics and pharmacodynamics of propofol are neither affected by the type of oil nor by the concentration of propofol in an intravenous formulation. While significantly increasing the amount of oil may aid in reducing pain on injection, oil levels as high as 20% are likely to further compromise patients undergoing prolonged administration of propofol, for example in intensive care units, and potentially lead to hyperlipidemia in those patients.
Haynes in U.S. Pat. No. 5,637,625 recognized two problems associated with the use of large quantities of vegetable oil in the commercial DIPRIVAN formulation: hyperlipidemia in patients undergoing long-term sedation in an intensive care unit (ICU), and the risk of bacterial contamination and growth in the high lipid content formulation that lacked antimicrobial preservatives. U.S. Pat. No. 5,637,625 disclosed formulations of phospholipid coated micromatrices or microdroplets of propofol devoid of fats and triglycerides that provided anesthesia and chronic sedation over extended periods of time without fat overload. Haynes"" microdroplet formulations are bactericidal (e.g. self-sterilizing) in large part because they are free of material that will support bacterial growth. This gave the formulations an extended shelf life.
Three of the most often cited shortcomings of currently marketed or previously disclosed formulations are the potential for growth of microorganisms in the formulation, the induction of local irritation and/or pain at the site of injection, and the use of high levels of lipid.
This invention discloses compositions of sterilized, injectable homogenized dispersions of micromatrices or microdroplets containing propofol suspended in an aqueous medium and containing an antimicrobial agent. The micromatrices or microdroplets have a mean diameter from about 50 nm to about 1000 nm and consist essentially of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent with the proviso that the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5. The aqueous medium contains a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the final sterilized dispersion to be isotonic with blood. The viscosity of a composition of this invention is in the range from about 1.1 to 8 cps, preferably in the range from about 4 to 6 cps.
In preferred embodiments, the dispersions contain a synergetic quantity of antimicrobial agent. In one aspect, a synergetic quantity of antimicrobial agent can be characterized as an amount of antimicrobial agent below the threshold of efficacy of the antimicrobial agent. Antimicrobial efficacy is an ability to retard or inhibit microbial growth.
In one embodiment, the threshold of efficacy of an antimicrobial agent can be defined as the minimum amount of the antimicrobial agent which permits no more than a 0.5 log increase in microbial growth over at least 7 days (168 hours) from the level of an initial inoculum of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739 and ATCC 8454), Pseudomonas aeruginosa (ATCC 9027), Candida albicans (ATCC 10231), and Aspergillus niger (ATCC 16403) added at approximately 1000 colony forming units (CFU) per milliliter to a reference dispersion at a temperature in the range 20-25xc2x0 C. To identify a threshold of efficacy amount of an antimicrobial agent, a washed suspension of each organism is added to a separate aliquot of a homogenized reference dispersion of micromatrices or microdroplets consisting of a propofol-soluble diluent and an amphiphilic agent suspended in an aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the reference dispersion to be isotonic with blood, the ratio of propofol-soluble diluent to amphiphilic agent being substantially that of the propofol-containing dispersions of this invention. The inoculated reference dispersion is incubated at 20-25xc2x0 C. for up to 7 days, and viable colonies of the organism are counted at 24 hours after inoculation, at 48 hours after inoculation, and at 7 days or 168 hours after inoculation. A threshold of efficacy amount can be established by increasing or decreasing the concentration of antimicrobial agent to achieve no more than a 0.5 log increase as described above.
In another aspect the antimicrobial efficacy of an amount of antimicrobial agent at any concentration can be determined in a reference dispersion relative to its antimicrobial efficacy at higher and lower concentrations and relative to the same concentration in the presence and absence of propofol. If the antimicrobial activity of a dispersion of micromatrices or microdroplets of this invention containing propofol and an antimicrobial agent is greater than the sum of the antimicrobial activity of a reference dispersion of micromatrices or microdroplets containing propofol but without the antimicrobial agent plus the antimicrobial activity of a reference dispersion of micromatrices or microdroplets containing the antimicrobial agent but without propofol, then the antimicrobial activity of the dispersion of this invention is the result of a synergy among the components, and the amount of antimicrobial agent is a synergetic quantity. In this regard, a synergetic quantity thus can be an amount or concentration of antimicrobial agent above the threshold of efficacy amount in a composition of this invention.
The compositions of the invention are antimicrobial, inhibit or retard the growth of extrinsically added microbes such as bacteria and fungi, do not induce local irritation and/or pain at the site of injection, and do not contain high levels of lipid thereby substantially reducing the propensity of a patient to develop hyperlipidemia as a result of administration of propofol in the compositions relative to that of DIPRIVAN.
The compositions of this invention are useful for the production and maintenance of ambulatory anesthesia, neurosurgical anesthesia, neuroanesthesia and pediatric anesthesia; for monitored anesthesia care; for intensive care sedation; for general sedation, for cardiac anesthesia, for treatment of migraine headaches and cephalalgia, as antiemetics and the prevention of emesis, as well as other clinical uses.
Also disclosed are processes for the preparation of compositions of this invention. In one embodiment, a preferred process comprises, in the following sequence of steps, the formation of a lipophilic phase containing about 1% to about 7.5% propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent dissolved or dispersed therein with the proviso that in the dispersion the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5; the separate formation of an aqueous phase before, during, or after the formation of the lipophilic phase, which aqueous phase contains a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the final dispersion to be isotonic with blood and a synergetic quantity of an antimicrobial agent; the mixing of the lipophilic phase and the aqueous phase to form a premix; the homogenization of the premix to form a dispersion of micromatrices or microdroplets containing propofol and a propofol-soluble diluent, the micromatrices or microdroplets stabilized by surface stabilizing amphiphilic agent and suspended in an aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the final dispersion to be isotonic with blood, the dispersion also containing a synergetic quantity of antimicrobial agent; the dispensing of an aliquot of said dispersion into a vial followed by the sealing of said vial; and then terminal steam sterilization to form a sterilized final dispersion.
In another embodiment, the process comprises, in the following order, the formation of a lipophilic phase containing about 1% to about 7.5% propofol and about 1% to about 8% of a propofol-soluble diluent; the separate formation before, during, or after the formation of the lipophilic phase of an aqueous phase containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the final dispersion to be isotonic with blood, a synergetic quantity of an antimicrobial agent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent dissolved or dispersed therein with the proviso that the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5 in the final dispersion; the mixing of the lipophilic phase and the aqueous phase to form a premix; the homogenization of the premix to form a dispersion of micromatrices or microdroplets containing propofol and a propofol-soluble diluent stabilized by the surface stabilizing amphiphilic agent suspended in an aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the dispersion to be isotonic with blood, the dispersion containing a synergetic quantity of antimicrobial agent; the dispensing of an aliquot of said dispersion into a vial followed by the sealing of said vial; and a terminal steam sterilization step to form a sterile final dispersion.
The vials can be cooled to ambient temperature after thermal sterilization by a number of means including cooling by immersion in a bath of cooling water e.g., a bath maintained at ambient or other temperature below the sterilization temperature, or a bath of cooling water maintained with a temperature gradient such as xe2x88x921xc2x0 C. per minute to control the rate of cooling of the vials that were heated during sterilization. Alternatively, the vials may be cooled in ambient air such as in a sterile environment in a GMP approved manufacturing facility.
An aliquot of the dispersion can be from about 1 milliliter to about 1 liter or 2 liters, preferably from about 1 milliliter to about 500 milliliters, more preferably from about 5 milliliters to about 250 milliliters, and most preferably from about 10 milliliters to about 100 milliliters. A vial is preferably about 10 to 25% larger than the aliquot to be dispensed therein. Preferably, the process of preparing a dispersion of this invention is carried out in an inert, non-oxidizing atmosphere such as in a nitrogen or argon atmosphere. Preferably, the vials contain no oxygen, and the dispensing of the aliquots and sealing operations are done in an atmosphere of an inert gas such as nitrogen or argon. It is preferred that the amount of the dispersion of this invention in a sealed vial be slightly larger than the total amount of the dispersion to be withdrawn from the vial during expected or anticipated clinical use. By slightly larger we mean about 1 to 5% larger, preferably 1% to about 3% larger than the expected amount to be used. This allows the removal of a dose or repeated removal of doses required to achieve a clinically effective result while leaving a slight excess of the dispersion available to allow for dead volumes in a needle, syringe or giving set or similar device, and minimizes waste of amounts approximating a required effective amount or dose.
In one embodiment of a process of this invention, an antimicrobial agent can be added to the aqueous phase prior to the formation of the premix.
In another embodiment of a process of this invention, an antimicrobial agent can be added to the premix prior to homogenization of the premix and formation of the dispersion of micromatrices or microdroplets.
In another embodiment of a process of this invention, an antimicrobial agent can be added after homogenization of the premix and formation of the dispersion of micromatrices or microdroplets but prior to the aliquoting of the dispersion into vials.
In another embodiment of a process of this invention, an antimicrobial agent can be added to a vial, optionally in pure form or in the form of an aqueous solution or in the form of a suspension compatible with the dispersion of micromatrices or microdroplets containing propofol, which dispersion is then added to the vial.
A solution or suspension containing the antimicrobial agent and compatible with the dispersion may also contain one or more pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient, preferably the excipient that is used in the dispersion.
A solution or suspension containing the antimicrobial agent and compatible with the dispersion may contain one or more pharmaceutically acceptable surface stabilizing amphiphilic agent, preferably the surface stabilizing amphiphilic agent used in the dispersion.
A suspension containing the antimicrobial agent and compatible with the dispersion may contain one or more propofol-soluble diluent together with one or more pharmaceutically acceptable surface stabilizing amphiphilic agent in the form of a suspension of micromatrices or microdroplets of propofol-soluble diluent stabilized with one or more pharmaceutically acceptable surface stabilizing amphiphilic agent. Preferably, the diluent is the same as that used in the dispersion or preferably the amphiphilic agent is the same as that used in the dispersion. More preferably, both the diluent and the amphiphilic agent are the same as those used in the dispersion.
A suspension compatible with the dispersion may contain a more concentrated dispersion of the propofol-containing micromatrices or microdroplets of this invention, i.e., it can have less water. The process of mixing two compatible dispersions, one of which is a concentrated dispersion and one of which is a diluting dispersion, results in a dilution of the more concentrated dispersion. Preferably the ratio of propofol to diluent and the ratio of propofol to amphiphilic agent of the concentrated and diluting dispersion are the same in each dispersion. The dispersions are thus substantially similar except for the amount of water in each, the concentrated dispersion having less water and the diluting dispersion having more water, and except for the presence of antimicrobial agent in the concentrated dispersion.
In another embodiment of this invention, a first dilute dispersion not containing an antimicrobial agent and a second concentrated dispersion containing an antimicrobial agent are prepared and are then mixed together. In this embodiment, a first dilute dispersion can contain micromatrices or microdroplets of propofol and a propofol-soluble diluent and be stabilized with an amphiphilic agent. The first dispersion can be prepared by homogenizing the components in an aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient. Homogenization can be by a process using high sheer such as high-pressure homogenization, microfluidization, sonication, and the like. A second, concentrated dispersion containing micromatrices or microdroplets of propofol and a propofol-soluble diluent and stabilized with an amphiphilic agent can be prepared by homogenizing the components in an aqueous medium optionally containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient and an antimicrobial agent where the amount of water in the first, diluted dispersion is less than the amount of water in the second dispersion. The amount of water in the second dispersion can be from about 10% to about 95% of the amount of water in the first dispersion. A portion of the first dispersion can be mixed with an aliquot of the second dispersion to achieve a composition of this invention that can be sterilized to achieve a final dispersion. The mixing of the dispersions can be done in bulk prior to dispensing into vials followed by sealing of the vials and sterilization or it can be done in individual vials prior to sterilization. The ratio of the amounts of first dispersion and second dispersion and the amount of pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in each can be selected to achieve a composition having ratios and concentrations according to this invention.
Percentages of ingredients used in the description of this invention are meant to be the percentages of the ingredients in the final dispersion. Actual amounts and relative amounts used can be readily calculated by one skilled in the art.
In another embodiment of a process of this invention, a first dispersion of micromatrices or microdroplets containing propofol can be prepared according to this invention but made to contain a concentrated amount of antimicrobial agent. This first dispersion can be added to a second dispersion of propofol micromatrices or microdroplets containing a propofol-soluble diluent and stabilized by a surface stabilizing amphiphilic agent prepared in a manner similar to or according to this invention but without the addition of an antimicrobial agent, or prepared by a method otherwise known in the art without the addition of an antimicrobial agent, to provide a final composition according to this invention containing an amount of antimicrobial agent wherein the diluted amount is a synergetic quantity of antimicrobial agent. The concentrated amount of antimicrobial agent can be for example a 2 fold amount to a 100 fold amount relative to a desired synergetic amount, and the dilution can be from about 100 fold to about 2 fold to achieve the desired synergetic amount or concentration in the final dispersion.
Additional process can be envisioned to prepare compositions of this invention that involve variations of the concentration of the dispersion, the amount of water, and the individual ingredients as well as the order of mixing of the ingredients. Such variations are anticipated by this invention.
Also disclosed in this invention are methods of treatment or methods of use of compositions of this invention. Thus, disclosed are a method for the production and maintenance of ambulatory anesthesia in a patient; a method for the production and maintenance of neurosurgical anesthesia in a patient; a method for the production and maintenance of anesthesia in a pediatric patient; a method for the production and maintenance of anesthesia in monitored care of a patient; a method for the production and maintenance of sedation of a patient in intensive care; a method for the production and maintenance of general sedation in a patient; a method of treatment and alleviation of a migraine headache in a patient; and a method of treatment and alleviation of emesis in a patient. The patient can be a human or an animal, and the method can optionally be practiced in a hospital setting for a human patient and a veterinary clinic or hospital for an animal. Animals include domestic animals such as a dog, cat, horse, cow, sheep, pig, and wild animals such as those kept in zoos such as lions, tigers, bears, monkeys, apes and the like.
A method of use or a method of treatment of a patient with compositions of this invention comprises administering to a patient by intravenous injection a composition of a sterilized, injectable homogenized dispersion of micromatrices or microdroplets containing propofol suspended in an aqueous medium, the micromatrices or microdroplets having a mean diameter from about 50 nm to about 1000 nm and consisting essentially of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent with the proviso that the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5, the aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the dispersion to be isotonic with blood, the viscosity of the dispersion being in the range from about 1.1 to 8 cps, the dispersion also containing a synergetic quantity of antimicrobial agent, which homogenized dispersion does not induce irritation or pain at the site of injection and does not enhance induce hyperlipidemia in the patient.
A method of treatment can comprise the injection into a patient of a composition of this invention. The injection can be in a bolus form or it can be administered by infusion in an aqueous liquid, preferably an aqueous liquid isotonic with blood, such as in an aqueous solution of a nutrient or electrolyte or phosphate buffered saline or other liquid infused during treatment of a patient such as before, and/or during, and/or after a surgical procedure; or as part of a life maintenance procedure; or during and/or after a hydration procedure; or as part of a treatment with an intravenously administered nutrition supplement. The injection can be made contiguous with an invasive surgical procedure, cancer surgery, dental surgery, treatment of a patient with a burn, treatment of a patient suffering from the effect of a crush injury, treatment of a patient suffering from the effect of an automobile accident or an accidental fall, treatment of patients undergoing cosmetic or restorative surgery, and other surgical procedures. Optionally, the aqueous dispersion can be mixed with or can contain other drugs such as other anesthetic agents such as lidocaine.
In another embodiment, a method of use of this invention comprises administering to a patient by intravenous injection a composition of a sterilized, injectable homogenized dispersion of micromatrices or microdroplets containing propofol suspended in an aqueous medium, the micromatrices or microdroplets having a mean diameter from about 50 nm to about 1000 nm and consisting essentially of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent with the proviso that the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5, the aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the dispersion to be isotonic with blood, the viscosity of the dispersion being in the range from about 1.1 to 8 cps, the dispersion also containing a synergetic quantity of antimicrobial agent, which dispersion does not induce irritation or pain at the site of injection and does not enhance or induce hyperlipidemia in the patient wherein the composition is withdrawn by a syringe with a needle from a sealed vial by puncturing a seal on the vial containing the composition, the contents of the syringe then being administered to the patient.
In another embodiment, a method of use of this invention comprises administering to a patient by intravenous injection a composition of a sterilized, injectable homogenized dispersion of micromatrices or microdroplets containing propofol suspended in an aqueous medium, the micromatrices or microdroplets having a mean diameter from about 50 nm to about 1000 nm and consisting essentially of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent with the proviso that the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5, the aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the dispersion to be isotonic with blood, the viscosity of the dispersion being in the range from about 1.1 to 8 cps, the dispersion also containing a synergetic quantity of antimicrobial agent, which dispersion does not induce irritation or pain at the site of injection and does not enhance or induce hyperlipidemia in the patient wherein the composition is withdrawn by a syringe with a needle from a sealed vial by puncturing a seal on the vial containing the composition, the contents of the syringe then being administered to the patient, wherein seal on the vial has been previously punctured by a syringe needle.
In another method of use of this invention, a first aliquot or dose of a dispersion of this invention is removed from a sealed vial by means of a first needle such as a syringe needle that punctures the seal on the vial, and the first aliquot or dose is then administered intravenously to a patient. Subsequently, a second aliquot or dose of the dispersion in the vial is removed by means of a second needle puncturing the previously punctured seal on the vial, and the second aliquot or dose is administered to a patient which can be the same patient that received the first aliquot or a second patient. The two doses can be the same amount of dispersion or different amounts, preferably anesthetically effective amounts or sedatively effective amounts. The process of puncturing the seal on the vial with a needle and removing an aliquot or dose of dispersion can be repeated until substantially all of the useful doses of the dispersion in the vial are withdrawn. The time period can be up to 168 hours during which the process of puncturing the seal on the vial and removing aliquots or doses of dispersion in the vial can be repeated after the initial puncture of the seal, preferably the time period can be up to 48 hours, and most preferably up to 24 hours.
It is an advantage that portions or aliquots or doses (including equal or unequal doses) of the contents of a vial containing a composition of this invention can be separately removed from the vial by separate punctures of the seal on the vial by a method employing a needle for each puncture. The compositions of this invention prevent or inhibit growth of extrinsically added microbes such as bacteria and fungi that may be introduced or inoculated into the composition as a result of repeated puncturing of the seal on the vial. The antimicrobial activity of the composition derives from a synergetic combination of antimicrobial activity of the antimicrobial agent and the antimicrobial activity of the propofol dispersion inherent in the composition in the absence of the antimicrobial agent.
In one aspect of this invention, the combination of antimicrobial activity of the antimicrobial agent and the antimicrobial activity of the propofol dispersion inherent in the composition in the absence of the antimicrobial agent is additive, particularly when the concentration of antimicrobial agent is below the threshold of efficacy described herein. In a preferred aspect, the combination of antimicrobial activity of the antimicrobial agent and the antimicrobial activity of the propofol composition inherent in the composition in the absence of the antimicrobial agent is synergetic, with the total antimicrobial activity being greater than the sum of the antimicrobial activity of the antimicrobial agent and the antimicrobial activity of the propofol composition inherent in the composition in the absence of the antimicrobial agent.
In another aspect the invention comprises a method for synergetically increasing the antimicrobial activity of a composition of a sterilized, injectable homogenized dispersion of micromatrices or microdroplets containing propofol suspended in an aqueous medium, the micromatrices or microdroplets having a mean diameter from about 50 nm to about 1000 nm and consisting essentially of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent with the proviso that the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5, the aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the dispersion to be isotonic with blood, the viscosity of the dispersion being in the range from about 1.1 to 8 cps, the method comprising the addition to the dispersion of a synergetic quantity of antimicrobial agent, which dispersion does not induce irritation or pain at the site of injection and does not enhance induce hyperlipidemia in the patient.
In one aspect, this invention provides a method of synergetically increasing the antimicrobial efficacy against microbial growth in a stable, sterilized, substantially non-irritating, injectable, homogenized dispersion of micromatrices or microdroplets containing propofol suspended in an aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the dispersion to be isotonic with blood, by incorporating a synergetic quantity of a water-soluble or partially water-soluble antimicrobial agent into the dispersion, wherein said micromatrices or microdroplets have a mean diameter from about 50 nm to about 1000 nm and are comprised of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent in which the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5, and wherein the viscosity of the dispersion is in the range of 1.1 to 8 cps.
In another aspect, this invention provides a method of synergetically increasing the antimicrobial efficacy against microbial growth in a vial or giving set in contact with a stable, sterilized, substantially non-irritating, injectable, homogenized dispersion of micromatrices or microdroplets of propofol suspended in an aqueous medium containing a pharmaceutically acceptable water-soluble hydroxyl-group-containing excipient in an amount sufficient to adjust the osmolality of the dispersion to be isotonic with blood, by incorporating a synergetic quantity of a water-soluble or partially water-soluble antimicrobial agent into the dispersion, wherein said micromatrices or microdroplets have a mean diameter from about 50 nm to about 1000 nm and are comprised of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent in which the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5, and wherein the viscosity of the dispersion is in the range of 1.1 to 8 cps. In this aspect the vial can be sealed and steam sterilized, and then the seal of the vial can be punctured by a needle at least once such as by a syringe needle used to withdraw an aliquot or dose of the dispersion from the vial or to allow the contents of the vial to be removed in whole or in part. The seal of the vial can be punctured by a needle at least twice (i.e., two or more times) such as by a syringe needle used to repeatedly withdraw aliquots or doses of the dispersion from the vial.
The antimicrobial agent useful in this invention can be a single agent or a combination of one or more antimicrobial agents. The antimicrobial agent can be water-soluble or partially water-soluble. The antimicrobial agent can be completely dissolved in the aqueous medium of a composition of this invention or can be partly dissolved in the aqueous medium of a composition of this invention. In one embodiment, if the antimicrobial agent is partly dissolved in the aqueous medium, a portion of the antimicrobial agent that is not dissolved in the aqueous medium can reside in the micromatrices or microdroplets containing propofol or in micromatrices or microdroplets containing a propofol-soluble diluent. In another embodiment, the antimicrobial agent can reside is structures stabilized by a surface stabilizing amphiphilic agent such as in one or more bilayer structures and structures containing amphiphilic agent such as those described in U.S. Pat. No. 5,091,188.
The micromatrices or microdroplets containing propofol of this invention have a mean diameter from about 50 nm to about 1000 nm, preferably from about 50 nm to about 800 nm, and consist essentially of about 1% to about 7.5% of propofol, about 1% to about 8% of a propofol-soluble diluent, and about 0.67% to about 5% of a surface stabilizing amphiphilic agent with the proviso that the ratio of propofol to diluent is in the range of about 0.25 to about 7.5 while the ratio of propofol to amphiphilic agent is in the range from about 0.4 to about 1.5.
Surprisingly, in this invention certain propofol compositions each prepared as an injectable aqueous dispersion of a water-insoluble micromatrix or dispersion consisting of propofol and one or more propofol-soluble agents or diluents and one or more antimicrobial agents present in a synergetic quantity in the dispersion are capable of substantially limiting or inhibiting the growth of certain microorganisms to a substantially greater degree or extent than is otherwise expected from the antimicrobial property or antimicrobial activity of the propofol formulation alone or from the antimicrobial activity of the antimicrobial agent alone in the concentrations defined herein. Furthermore, it is surprising that the compositions of this invention containing a combination of a dispersion containing propofol plus antimicrobial agent do not display evidence of local irritation at the injection site.